Purpose This Funding Opportunity Announcement (FOA) encourages Small Business Innovation Research (SBIR) grant applications from small business concerns (SBCs) that propose to implement investigator-initiated clinical trials, including mechanistic studies associated with clinical trials. A clinical trial is defined by NIH as: "A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes." See more at: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html#sthash.W5hQ9GMA.dpuf In addition, any research study that will require a regulatory oversight (such as Investigational New Drug [IND] or Investigational Device Exemption [IDE]) will be in the scope of this FOA. This program provides support for milestone-driven, hypothesis-driven clinical trials related to the research mission of the NIAID that address a research area considered high priority by the Institute. Applicants seeking a Phase II renewal or Phase IIB renewal must have received an eligible predicate award that is appropriate and relevant (e.g., pre-clinical studies, planning activities, etc.) to this FOA. Although clinical trials not considered high-risk (see NOT-AI-16-084) may be proposed, this program encourages high-risk clinical studies. High-risk does not imply human subject or patient risk, but rather defines a study that contains one or more of the following unique attributes: involves non-routine interventions, administration of an unlicensed product, or administration of a licensed product for an unapproved indication. Additionally, mechanistic studies are encouraged and can be proposed under this program. Applicants may not propose more than one clinical trial per application. Background Over the past three years, NIAID has committed over $5.5 billion to clinical research, of which $2.5 billion was devoted to clinical trials and supportive activities. Clinical trials are one research strategy NIAID uses to improve the understanding of the clinical mechanisms of infectious, immunologic, and allergic diseases or to improve prevention, diagnosis, and treatment. For additional information about the mission, strategic plan, and research interests of the NIAID, applicants are encouraged to consult the NIAID web site https://www.niaid.nih.gov/research/role. NIAID Supported Clinical Trials and Infrastructure Historically, NIAID supports both infrastructure and networks through a variety of funding mechanisms. These resources focus on high-priority disease research areas. Examples include the HIV/AIDS Clinical Trial Networks supported by the Division of AIDS (DAIDS), the Division of Microbiology and Infectious Diseases (DMID) Infectious Diseases Clinical Research Consortium, and the Immune Tolerance Network supported by the Division of Allergy, Immunology and Transplantation (DAIT). NIAID's clinical research infrastructure includes coordinating centers, statistical units, data centers, central laboratories, clinical centers, and other specialized resources. For additional information on DAIDS supported clinical trials refer to the Division of AIDS (DAIDS) Clinical Research Policies and Standard Procedures Documents. For additional information on DAIT Clinical Research Policies and Documents see: https://www.niaid.nih.gov/research/dait-clinical-research-policies-and-standards. Investigator-Initiated Clinical Trials Although existing clinical trial programs and infrastructure are crucial to furthering the Institute's research, the NIAID recognizes that additional means to support clinical research may be important to advancing its research mission. Therefore, the NIAID has established the investigator-initiated clinical trial program for clinical trials that cannot or will not be conducted through existing NIAID-supported clinical trial networks or infrastructure. For additional information about NIAID's investigator-initiated clinical trial program, see https://www.niaid.nih.gov/grants-contracts/investigator-initiated-clinical-trial-resources. Scope The NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement (U44) program provides a unique and focused opportunity for small business concerns (SBCs) interested in conducting clinical trials. This FOA supports implementation of clinical trials from small business concerns (SBCs) that propose clinical trials in research areas that are well matched with the mission and goals of the NIAID. The proposed clinical trial should be hypothesis-driven and milestone-driven. All clinical trial planning activities must be completed prior to the time of application submission and all requested documentation needs to be provided for an application to be considered complete for a Phase II award (except for Fast Track applications). Investigators are referred to NIAID's Clinical Research Toolkit website for protocol templates and guidance, clinical research resources, and links to program divisions. Investigators are strongly encouraged to contact the NIAID Scientific/Research Contact(s) for information regarding division-specific clinical research policies and procedures. This FOA will support the conduct, completion, and analysis of a clinical trial, including activities related to the conduct of the clinical trial, which include but are not limited to the following: training of study personnel; enrollment and recruitment of study subjects; investigational product costs; data collection, management and quality control; laboratory work and data analyses; study management and oversight; establishment of committees to manage the complexity of the trial; preparation of the final study report; and other related post-trial activities regulatory activities and site monitoring can be covered if required. mechanistic studies, if applicable Each NIAID Clinical Trial Implementation award will support the implementation of a single clinical trial that may include more than one intervention. Applications that include more than one clinical trial will not be supported by this FOA. All clinical trial planning activities must be completed prior to the time of application submission and investigators must be ready to implement the proposed trial at the time of award. NIAID reserves the right to specify: 1) whether an IND/IDE application should be submitted to an appropriate regulatory agency; 2) the entity (NIAID, primary awardee, etc.) who will hold the IND/IDE; 3) the requirements for the establishment of a DSMB (Data Safety Monitoring Board)/SMC (Safety Monitoring Committee) or the use of an NIAID sponsored DSMB; and 4) the use of other clinical resources such as a Statistical and Clinical Coordinating Center. Applicants are encouraged to discuss those decisions and requirements with NIAID prior to submission of the application. Mechanistic studies will be supported as part of all clinical trials in this FOA. DAIT strongly encourages the inclusion of mechanistic studies in any DAIT supported trials. Investigators are referred to the Division-specific research policies and standard procedures for protocol templates, guidance, and requirements for clinical trials. See Division of AIDS (DAIDS) Clinical Research Policies and Standard Procedure Documents; Division of Microbiology and Infectious Diseases (DMID) Office of Clinical Research Affairs; Division of Allergy, Immunology, and Transplantation (DAIT) Clinical Research Policies and Standards. Investigators are also referred to NIAID's Clinical Research Toolkit website https://www.niaid.nih.gov/research/trans-niaid-clinical-research-toolkit. Prior to initiation, protocols and consent forms may be subject to review by the NIAID Division. Investigators are strongly encouraged to contact NIAID's program divisions (Agency Contacts) for more information regarding division-specific clinical research policies and procedures. Milestones Delineation of milestones is a key characteristic of awards made in support of the NIAID's investigator-initiated clinical trial program, including this NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement (U44) FOA.A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Proposed clinical trial milestones provide a clear delineation of the criteria used to identify completed activities, but also provide for contingency plans to accommodate anticipated impediments that could require a revision in the timeline. Recognizing and indicating potential problems and obstacles are important aspects in identifying and discussing alternative approaches. The milestones will undergo peer review and will be incorporated into the terms of award. Applications Not Responsive to This FOA The following research activities are not responsive to this FOA and will not be reviewed: Applications proposing clinical trial planning tasks (except Fast Track applications), such as: Development of study design; Identification of collaborators and enrollment sites; Development of the clinical protocol and informed consent form; Development of the statistical analysis plan; Development of the data management plan; Development of the Investigator's brochure or equivalent; Applications that propose clinical trials that fall outside the mission and goals of the NIAID; Applications that propose clinical trials that will utilize dedicated resources that are part of an existing NIAID-supported clinical trial network; or Applications that propose more than one clinical trial. All research and development activities associated with awards made under this NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement (U44) FOA must be performed within the United States (the United States is defined as the 50 States, the territories and possessions of the United States, the Commonwealth of Puerto Rico, the Federated States of Micronesia, the Republic of Palau, the Republic of the Marshall Islands, and the District of Columbia). For more information, please see the Investigator-Initiated Clinical Trial Questions and Answers at: https://www.niaid.nih.gov/grants-contracts/investigator-initiated-clinical-trials-faqs.